Clinical evidence and implementation challenges for pharmacogenomic testing

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September 18, 2019 – This post is an edited version of parts of a paper that appeared in the Journal of Personalised Medicine (JPM) a week ago und which addresses one of the important topics in connection with the themes of personalised medicine, sometimes and interchangeably referred to as precision medicine or theragenomic medicine (you name it).

Pharmagenomics: the genetically transparent patient in heath and disease.

As the scientific approach underlying all these new forms of medicine, pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and lowering risk of serious adverse events. As of June 2019, there are 132 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels; these informations are constantly updated and extended (a good first entry point would be at PharmGKB). Recently, the technology for identifying individual-specific genetic variants (genotyping) has become more accessible. Next generation sequencing (NGS) is a cost-effective option for genotyping patients at many pharmacogenomic loci simultaneously, and guidelines for implementation of these data are available from organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). NGS and related technologies are increasing knowledge in the research sphere, yet rates of genomic literacy remain low, resulting in a widening gap in knowledge translation to the patient. In fact, despite the increased interest in genetics in the public sphere, driven by multiple factors, including direct-to-consumer testing, advances in genetic engineering, accumulating evidence of the importance of pharmacogenomics to successful pharmacological treatment, and the explosion of popular science journalism, the rate of adoption of pharmacogenomic testing in the clinical setting has been uneven.

Most worrying in this context is an apparent significant gap in genomic literacy among medical doctors and other health care professionals. Indeed, only 1 in 10 physicians (N > 10,000, response rate: 3%) responding to a USA-based survey reported feeling confident in their knowledge of pharmacogenomics and its clinical application; less than 1 in 3 physicians had ever ordered a pharmacogenetic test, and only 1 in 8 physicians had recommended or ordered a test in the previous six months.
Overall, barriers to implementation of pharmacogenomic testing by physicians in everyday private practice or in the clinical setting fall into two broad categories: 1) answering the question of whether the testing should be performed at all, a point related to sufficiency of available evidence and cost-effectiveness, and 2) challenges associated with integration into the clinical system and work flow (such as the difficulty faced by clinical labs to comply with regulatory frameworks originally designed for non-genetic or single-gene tests).
This article highlights some of the factors that complicate an easy adaption of  pharmacogenomic testing into clinical practice. This is not intended to be an exhaustive review on how to surmount many of these barriers; we would, however, like to rise awareness for the complexity of application of pharmacogenomics in personalized and/or precision medicine, and why perhaps your treating physician or you as a patient may be hesitant to order a genetic test right away. Such factors are originating from the science behind pharmacogenomics per se, from unknown effects of pharmacogenomics on health care systems and regulations thereof, and from fears on the effects on patients privacy, as grouped together and listed below:
  • Lack of evidence of clinical validity of pharmacogenomic testing, including a lack of validated, pharmacogenomic-guided, treatment algorithms;
  • Identification of increased disease risks incidental to pharmacogenomic testing (e.g., BRCA1/BRCA2germline genetic test results to guide treatment also confer increased disease risk);
  • Complexity in pharmacogenomic test results, with attendant difficulties in interpretation, including the complex architecture of pharmacogenes such as, for example CYP2D6, and the potential for interactions with other prescribed medications known to impact on gene or enzyme function;
  • Lack of evidence regarding how to combine results from multiple pharmacogenes.
  • Lack of evidence demonstrating cost-effectiveness of pharmacogenomic testing and its impact on cost to a public healthcare system, private health insurance companies, and out-of-pocket patient costs);
  • Perceived or actual financial conflicts of interest for authors of research/guidelines supporting the utility of pharmacogenomic testing;
  • Lack of recommendations/regulations from professional organizations and health authorities to support clinicians in determining whether a pharmacogenomic test is appropriate;
  • Discrepancies between pharmacogenomic guidelines of different organizations;
  • Ambiguity in how to clinically apply pharmacogenomic biomarker information in drug labels.
  • Lack of expertise amongst prescribing clinicians to determine how to handle patients genetic privacy (i.e., medical records);
  • Lack of patients confidence into his/her “genetic” privacy.
We believe thatharmacogenetics holds considerable, largely untapped potential to firstly avoid adverse drug responses, to secondly optimize medication selection and dosing, and thirdly to target therapies to the right patient (particularly but not exclusively in oncology). While it is difficult to predict how quickly and broadly pharmacogenomic testing will be adopted in different countries and contexts, it is very promising that large scale implementation efforts to address health-systems integration challenges associated with pharmacogenomic testing are currently underway, at least on a research basis, in the US (e.g., PGRN’s Translational Pharmacogenomics Program), the “Right Drug, Right Dose, Right Time” Protocol (RIGHT Protocol), the PREDICT program, the NIH’s All of Us Project), and in Europe the Ubiquitous Pharmacogenomics Project (UPGX).
In addition, the pharmacogenomics community needs to do everything we can to identify and engage allies, across healthcare disciplines, in pushing for systemic and cultural change. There is a collective responsibility to ensure that the potential health benefits of pharmacogenomics reach beyond early-adopter and privileged niches. In striving towards this goal, it is important to note that the vast majority of available data have been collected from primarily White populations. Given that we know that the reference genome and associated variants are missing over 300 million bases for other populations (e.g. Asiatic, African, Indigenous, etc.), it will be essential to continually update the statistics on population-specific variant frequencies, and reconsider implications for guidelines and clinical practice in light of these new data.
Huge efforts will also be necessary in the communication between stake holders, particularly with patients, in order to understand the value of preemptive pharmacogenomic testing and of the ensuing test results. Thus, in a recent study interviewing about 1000 patients, 26 percent said that they only somewhat understood their pharmacogenomic results and 7% reported they did not understand them at all. Only education predicted understanding. The most common suggestion for improvement was the use of layperson’s terms when reporting results. In addition, responders suggested that results should be personalized by referring to medications that they were currently using. Of those reporting imperfect drug adherence, most (91%) reported they would be more likely to use medication as prescribed if pharmacogenomic information was used to help select the drug or dose.
In this of a multidisciplinary network of affected patients,  treating physicians, pharmacogenomics experts,, and representants of health care and insurance providers, there may be an important role for particularly able genetic counsellors, who may integrate the different languages talked by all these involved stakeholders in the quest to make pharmacogenomics a success and to have the patient benefit the most. For the US and Canada, you may already consult directories available through the US-based National Society of Genetic Counselors website or the Canada-based Canadian Association of Genetic Counsellors website  for genetic counsellors.
See here a short sequence by a true pioneer in pharmacogenomics:

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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